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Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation
Author(s) -
Benelli Roberto,
Morini Monica,
Carrozzino Fabio,
Ferrari Nicoletta,
Minghelli Simona,
Santi Leonardo,
Cassatella Marco,
Noonan Douglas M.,
Albini Adriana
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0651fje
Subject(s) - angiostatin , angiogenesis , chemokine , chemotaxis , inflammation , in vivo , chemistry , cancer research , immunology , receptor , biology , biochemistry , microbiology and biotechnology
ABSTRACT Angiostatin effectively blocks tumor angiogenesis through still poorly understood mechanisms. Given the close association between immune and vascular regulation, we investigated the effects of angiostatin on angiogenesis‐associated leukocytes. Angiostatin inhibited the migration of monocytes and, even more markedly, neutrophils. Angiostatin blocked chemotaxis of neutrophils to CXCR2 chemokine receptor agonists (IL‐8, MIP‐2, and GROα), formyl‐Met‐Leu‐Phe (fMLP), and 12‐O‐tetradecanoylphorbol 13‐acetate, and repressed fMLP‐induced mitochondrial activity. Two different angiostatin forms (kringles 1–4 and 1–3) were effective, whereas whole plasminogen had no effect. IL‐8, MIP‐2, and GROα induced intense angiogenic reactions in vivo, but no angiogenic response to these factors was observed in neutropenic mice, demonstrating an essential role for neutrophils. Angiostatin potently inhibited chemokine‐induced angiogenesis in vivo, and consistent with in vitro observations, both angiostatin forms were active and whole plasminogen had little effect. Angiostatin inhibition of angiogenesis in vivo was accompanied by a striking reduction in the number of recruited leukocytes. In vivo, the inflammatory agent lipopolysaccharide also induced extensive leukocyte infiltration and angiogenesis that were blocked by angiostatin. Neutrophils expressed mRNAs for ATP synthase and angiomotin, two known angiostatin receptors. These data show that angiostatin directly inhibits neutrophil migration and neutrophil‐mediated angiogenesis and indicate that angiostatin might inhibit inflammation.